The overall objective of the research described is to better understand the biochemical mechanism(s) by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds produce toxicity in animals. More specifically, studies will determine whether altered absorption or utilization of nutrients from the gastrointestinal tract mainly contributes to weight loss and subsequent lethality in TCDD-treated animals. This will be tested by determining the effect of total parenteral nutrition (TPN) on weight gain, gross and histopathology, and mortality in TCDD-treated guinea pigs. Other studies will examine if the altered disposition of nutritional substrates and/or tissue iron stores may contribute to hepatic damage and lethality in TCDD-treated rats. This will be performed by specific alterations in the composition of the TPN diet as well as promoting iron deficiency by the inclusion of a specific iron chelator in this diet. Other proposed studies will more clearly define and quantitate the dose and time related changes in serum and hepatic lipid alterations in TCDD-treated rats and mice. Emphasis will be placed on alterations in cholesterol metabolism. These studies will be extended to characterize the effect of TCDD on lysosomal acid lipase which hydrolyzes cholesteryl esters, and will determine if this effect is specifically on the lipase or on general lysosomal function. Additional studies focusing on structure-activity relationships and responses in genetic strains of mice will investigate if the effect upon cholesterol metabolism and lysosomal function is related to the ability of TCDD and related compounds to bind to a cytosolic receptor protein and induce various enzymatic systems. Studies will also examine whether the hypoglycemia observed in TCDD-treated rats is due to a decreased synthesis and/or increased tissue uptake and catabolism of serum glucose. Hormonal levels, concentrations of gluconeogenic precursors, and enzymatic pathways which may lead to this hypoglycemia will be examined.